Thursday, November 26, 2009

“Feeding the clock - Science Centric” plus 4 more

“Feeding the clock - Science Centric” plus 4 more

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Feeding the clock - Science Centric

Posted: 26 Nov 2009 01:15 AM PST

When you eat may be just as vital to your health as what you eat, found researchers at the Salk Institute for Biological Studies. Their experiments in mice revealed that the daily waxing and waning of thousands of genes in the liver - the body's metabolic clearinghouse - is mostly controlled by food intake and not by the body's circadian clock as conventional wisdom had it.

'If feeding time determines the activity of a large number of genes completely independent of the circadian clock, when you eat and fast each day will have a huge impact on your metabolism,' says the study's leader Satchidananda (Satchin) Panda, Ph.D., an assistant professor in the Regulatory Biology Laboratory.

The Salk researchers' findings, which will be published in a forthcoming issue of the Proceedings of the National Academy of Sciences, could explain why shift workers are unusually prone to metabolic syndrome, diabetes, high cholesterol levels and obesity.

'We believe that it is not shift work per se that wreaks havoc with the body's metabolism but changing shifts and weekends, when workers switch back to a regular day-night cycle,' says Panda.

In mammals, the circadian timing system is composed of a central circadian clock in the brain and subsidiary oscillators in most peripheral tissues. The master clock in the brain is set by light and determines the overall diurnal or nocturnal preference of an animal, including sleep-wake cycles and feeding behaviour. The clocks in peripheral organs are largely insensitive to changes in the light regime. Instead, their phase and amplitude are affected by many factors including feeding time.

The clocks themselves keep time through the fall and rise of gene activity on a roughly 24-hour schedule that anticipates environmental changes and adapts many of the body's physiological function to the appropriate time of day.

'The liver oscillator in particular helps the organism to adapt to a daily pattern of food availability by temporally tuning the activity of thousands of genes regulating metabolism and physiology,' says Panda. 'This regulation is very important, since the absence of a robust circadian clock predisposes the organism to various metabolic dysfunctions and diseases.'

Despite its importance, it wasn't clear whether the circadian rhythms in hepatic transcription were solely controlled by the liver clock in anticipation of food or responded to actual food intake.

To investigate how much influence rhythmic food intake exerts over the hepatic circadian oscillator, graduate student and first author Christopher Vollmers put normal and clock-deficient mice on strictly controlled feeding and fasting schedules while monitoring gene expression across the whole genome.

He found that putting mice on a strict 8-hour feeding/16-hour fasting schedule restored the circadian transcription pattern of most metabolic genes in the liver of mice without a circadian clock. Conversely, during prolonged fasting, only a small subset of genes continued to be transcribed in a circadian pattern even with a functional circadian clock present.

'Food-induced transcription functions like a metabolic sand timer that runs for 24 hours and is continually reset by the feeding schedule while the central circadian clock is driven by self-sustaining rhythms that help us anticipate food, based on our usual eating schedule,' says Vollmers. 'But in the real world we don't eat at the same time every day and it makes perfect sense to increase the activity of metabolic genes when you need them the most.'

For example, genes that encode enzymes needed to break down sugars rise immediately after a meal, while the activity of genes encoding enzymes needed to break down fat is highest when we fast. Consequently a clearly defined daily feeding schedule puts the enzymes of metabolism in shift work and optimises burning of sugar and fat.

'Our study represents a seminal shift in how we think about circadian cycles,' says Panda. 'The circadian clock is no longer the sole driver of rhythms in gene function, instead the phase and amplitude of rhythmic gene function in the liver is determined by feeding and fasting periods - the more defined they are, the more robust the oscillations become.'

While the importance of robust metabolic rhythms for our health has been demonstrated by shift workers' increased risk of developing metabolic syndrome, the underlying molecular reasons are still unclear. Panda speculates that the oscillations serve one big purpose: to separate incompatible processes, such as the generation of DNA-damaging reactive oxygen species and DNA replication.

Panda, for one, has stopped eating between 8 PM and 8 AM and says he feels great. 'I even lost weight, although I eat whatever I want during the day,' he says.

Source: Salk Institute

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International collaborative research projects to decipher the biology ... - News-Medical.Net

Posted: 26 Nov 2009 02:34 AM PST

UK Biotechnology and Biological Sciences Research Council and US National Institute on Aging

Research efforts to help the world's ageing population live longer healthier lives have been given a major boost with the announcement of six new transatlantic research projects aiming to understanding the biology of the ageing process.

In the first agreement of its kind, the US funding agency for ageing research, the National Institute on Aging (NIA) and the UK's funding body for bioscience research, the Biotechnology and Biological Sciences Research Council (BBSRC) are jointly funding £4M of projects. Each project includes leading researchers from universities from both the UK and US.

The transatlantic research teams will study the biology that drives how our bodies change with age. Their aim is to generate knowledge about the biology behind ageing that will ultimately contribute to a better quality of life and health for the growing older population.

Amongst the challenges that the projects will investigate are: why an older person's immune systems doesn't always work as well as a younger person's; what genetic and molecular effects in the body that determine age span; and how environmental factors impact on the genetics of ageing.

Professor Douglas Kell, BBSRC Chief Executive said: "We are seeing increased life expectancy in the developed world and a growing older population as a consequence. Living a long life is one thing, but living a healthy, active and enjoyable life into old age is quite another.

"To appreciate what older people need in order to remain healthy and active we must understand as much as we can about what is going on in an ageing body. With this knowledge, our clinical colleagues can develop healthcare and disease prevention strategies that will see older people on both sides of the Atlantic, and beyond, living fulfilled and happy lives. By working together, BBSRC and NIA have been able to capitalise on the world class research in both countries and leverage the funding available to our scientists."

NIA Director Richard J. Hodes, M.D. said: "We are excited to expand our scientific pursuits through this unique opportunity to work with our colleagues overseas. Research aimed at better understanding the nature of aging should help us find ways to extend the healthy, active years of life." As part of the National Institutes of Health, NIA leads the United States Federal effort in supporting and conducting research on aging and the medical, social, and behavioural issues of older people.

By combining researchers from the UK and US the projects bring together the best science from both sides of the Atlantic and capitalise on the different skill sets and assets each country has. The University of Glasgow and Brown University will work together to test a new biological theory of ageing; University College London and the University of Arizona will collaborate to study the decline in immunity of the skin of older people; the University of Edinburgh and the University of Georgia will examine the effects of fluctuating hormone levels on older people's immune systems; King's College London and the Georgia Institute of Technology will ask how environmental factors can impact the level of activity of certain genes involved in ageing; Bangor University and the University of Texas Health Science Centre, San Antonio are looking to the world's longest-lived animal, the ocean quahog, to ask what factors affect longevity and how can they lead to such a wide variation in lifespan; and Imperial College London and the University of Washington are focussing in on a molecular system in cells that is involved in healthy ageing.

Professor Kell continued: "We are really delighted to see these valuable international collaborations arise out of the joint sponsorship programme we set up with NIA. Science has become a truly global effort these days, and we are very happy to support researchers who are coming together to maximise effort and take full advantage of each other's strengths."

SOURCE UK Biotechnology and Biological Sciences Research Council and US National Institute on Aging

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Computational biology: Biological logic - Nature.com

Posted: 25 Nov 2009 10:59 PM PST

Published online 25 November 2009 | Nature 462, 408-410 (2009) | doi:10.1038/462408a

News Feature

An intuitive approach to computer modelling could reveal paths to discovery, finds Lucas Laursen.

Lucas Laursen

Grabbing one of the three laptops in her office at Microsoft Research in Cambridge, UK, Jasmin Fisher flips open the lid and starts to describe how she and her collaborators used an approach from computer science to make a discovery in molecular biology.

Fisher glances across her desk to where her collaborator, Nir Piterman of Imperial College London, is watching restlessly.

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Reader comments are usually moderated after posting. If you find something offensive or inappropriate, you can speed this process by clicking 'Report this comment' (or, if that doesn't work for you, email webadmin@nature.com). For more controversial topics, we reserve the right to moderate before comments are published.

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Students study the effects of alcohol on embryos - Centre College News & Events

Posted: 26 Nov 2009 06:23 AM PST

Students study the effects of alcohol on embryos

RELEASED: November 26, 2009

By Leigh Ivey

DANVILLE, KY—For the most recent lab assignment in his developmental biology course, assistant professor of biology Dr. Brian Storz took an uncommon approach.

Rather than asking students to simply examine slides of embryos and make observations about growth and development, he allowed his upper-level biology students to investigate firsthand the effects of fetal alcohol syndrome (FAS) on developing chick embryos.

"Basically, we're quantifying the effects of FAS on the embryos, the implications of which are directly related to human health," says Megan Gatewood '10 of Louisville. "We're measuring things like size of the eyes and heart rate. It's commonly known that birth defects are associated with FAS, but this experiment will show directly what developmental processes are affected."

On the first day of the experiment, the students explanted nine chick embryos from their eggs. They then added one milliliter of 0.1 percent alcohol to three embryos, a milliliter of one percent alcohol to three others, and no alcohol to the last three, which served as controls.  

Each day afterward, the students returned to the lab for observation and data collection.

Developed by Peter Armstrong at UC Davis, the experiment is one in which Storz himself participated as an undergraduate.

"It was definitely one of the labs that resonated with me for the rest of my life," he says. "It's one thing to look at images in a book and on slides, but to really be in touch with developmental biology, there's nothing like maintaining a living embryo through development—coming in every single day, checking on it, watching it grow and develop all its features, and seeing how similar it is to pictures of human embryos that students see every day in books."

Like most of the students taking part in the experiment, junior Ben Cocanougher of Springfield, Ky., enjoyed the interactive components of the three-week experiment.

"In Dr. Storz's labs, you don't just look at slides all day," he says. "He does a great job tying in the class lectures with real-life experiments, so this lab has had a much bigger impact on my memory than some. We're able to really understand now how embryonic development takes place."

And because Storz asked each pair of students to choose a different aspect of development to observe, the students were able to make numerous discoveries.

The 16 students taking part in the developmental biology course were juniors and seniors who have the biology background, Storz says, that enabled him to tell them, "Go do science."

Louisville native Amanda Stovall '11 explains Storz's techniques for leading lab projects.

"We're given the tools to work with, then we choose what to study and design our own methods," she says. "This allows us to work in areas of our own interests, and it's made me personally feel very involved in the research."

Jeff SoRelle '10 of Waco, Texas, agrees that the hands-on approach made this lab experiement exceptionally rewarding.

"The coolest part of this lab was how Dr. Storz empowered us to design our own experiment," he says. "Sometimes other labs can be 'cookbookish' because everyone just follows along doing the same things, knowing what the results will probably be. But here, we were doing an experiment without knowing what the outcomes would be. And this is the essence of science—looking at something interesting without knowing what will happen."

When the class began the experiment, the chick embryos were three-and-a-half days old. Seventeen days later, the lab project came to an end—and the students, who saw clear qualitative changes in the embryos they observed, had an enormous amount of data to analyze and present.

Stovall made a particularly interesting observation—and one that is important for research concerning fetal alcohol syndrome in humans—about the effects of alcohol on the vascularization of the extra-embryonic tissues.

"This is synonymous with mammalian placenta in that it's how the embryos receive nutrients for growth," she explains. "In general, ethanol decreased the vascularization—less blood vessels, which also proved to be more fragile—which restricted the amount of nutrients the embryo could pull from the yolk sac."

This, she notes, would ultimately hinder the chick's ability to develop properly.

"Although we used two different treatments of differing concentrations of ethanol, this data supports the hypothesis that the timing of exposure to ethanol proved to affect the vascularization more so than the amount."

This discovery relates to that made my another group, who found that there is a marked difference in the size of the embryo based on alcohol exposure; those exposed to the ethanol resulted in smaller embryo size.

"This correlates perfectly with human observations," Storz says. "FAS babies are smaller, and Amanda Stovall's research provides a mechanism for how this happens—reduced vascularization of the extra-embryonic tissues."

Knowing that the embryos would be unable to survive for more than 19 days, several students puzzled over how to transport an embryo into a shell to enable it to hatch. "The chicks have to peck on something to survive," Gatewood says, "so we're going to try to pour the chick into an eggshell to see if it'll allow it to hatch. No one's ever been able to hatch a chick this way, but we're going to try."

After the observation period was complete, Gatewood and Jessica Wheeler were, at least, successful in transporting their chick back into an egg. "The heartbeat was still strong," Gatewood says, "so we put it in an incubator to monitor for a few days, although the re-plant was ultimately unsuccessful."

Just as the fetal alcohol experiment resonated with Storz as an undergrad, it has made a tremendous impact on his own students, many of whom share the belief that it is a lab they will never forget.

"To actually watch the developmental process take place has been truly awe-inspiring," Stovall says, "and it's given me an appreciation for life that I think would be difficult to get elsewhere."

Have comments, suggestions, or story ideas? E-mail leigh.ivey@centre.edu with your feedback.

- end -

 

Founded in 1819, Centre College is ranked among the U.S. News top 50 national liberal arts colleges. Consumers Digest ranks Centre No. 1 in educational value among all U.S. liberal arts colleges. Centre alumni, known for their nation-leading loyalty in annual financial support, include two U.S. vice presidents and two Supreme Court justices. For more, visit http://www.centre.edu/web/elevatorspeech/

For news archives go to http://www.centre.edu/web/news/newsarchive.html.

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Knockouts in human cells point to pathogenic targets - PhysOrg

Posted: 26 Nov 2009 07:42 AM PST

Knockouts in human cells point to pathogenic targets

November 26, 2009 Knockouts in human cells point to pathogenic targets

Enlarge

In the rare human cell line used for this genetic screen, the cells have only one copy of each chromosome, except for chromosome 8, which has two copies. Because this cell line has only one copy of almost all of the chromosomes, it is ideal for efficiently making knockout human cells. Photo - Courtesy of the Whitehead Institute

(PhysOrg.com) -- Whitehead researchers have developed a new approach for genetics in human cells and used this technique to identify specific genes and proteins required for pathogens.

With the ability to generate knockout cells for most human , the authors were able to find genes used by to enter and kill human cells. The identification of such factors could aid the future development of new therapeutics to combat infectious disease.

Whitehead researchers have developed a new type of genetic screen for human cells to pinpoint specific genes and proteins used by pathogens, according to their paper in Science.

In most human cell cultures genes are present in two copies: one inherited from the father and one from the mother. Gene inactivation by mutation is therefore inefficient because when one copy is inactivated, the second copy usually remains active and takes over.

In yeast, researchers have it easier: they use yeast cells in which all genes are present in only one copy (haploid yeast).

Now Carette and co-workers have used a similar approach and used a human cell line, in which nearly all human chromosomes are present in a single copy.

In this rare cell line, Carette and co-workers generated mutations in almost all human genes and used this collection to screen for the host genes used by pathogens. By exposing those cells to influenza or to various bacterial toxins, the authors isolated mutants that were resistant to them. Carette then identified the mutated genes in the surviving cells, which code for a transporter molecule and an enzyme that the hijacks to take over cells.

Working with Carla Guimaraes from Whitehead Member Hidde Ploegh's lab, Carette subjected knockout cells to several bacterial toxins to identify resistant cells and therefore the genes responsible.

The experiments identified a previously uncharacterized gene as essential for by diphtheria toxin and exotoxin A toxicity, and a cell surface protein needed for cytolethal distending toxin toxicity.

"We were surprised by the clarity of the results," says Jan Carette, a postdoctoral researcher in the Brummelkamp lab and first author on the Science article. "They allowed us to identify new genes and proteins involved in infectious processes that have been studied for decades, like diphtheria and the flu. In addition we found the first human genes essential for host-pathogen interactions where few details are known, as is the case for cytolethal distending toxin secreted by certain strains of E. coli. This could be important for rapidly responding to newly emerging pathogens or to study pathogen biology that has been difficult to study experimentally."

Brummelkamp sees the work as only the beginning.

"Having knockout cells for almost all human genes in our freezer opens up a wealth of biological questions that we can look at," he says. "In addition to many aspects of cell biology that can be studied, knockout screens could also be used to unravel molecular networks that are exploited by a battery of different viruses and bacteria."

Provided by Massachusetts Institute of Technology (news : web)



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